These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Targeting BCR-ABL+ stem/progenitor cells and BCR-ABL-T315I mutant cells by effective inhibition of the BCR-ABL-Tyr177-GRB2 complex.
    Author: Chen M, Turhan AG, Ding H, Lin Q, Meng K, Jiang X.
    Journal: Oncotarget; 2017 Jul 04; 8(27):43662-43677. PubMed ID: 28599273.
    Abstract:
    Treatment of BCR-ABL+ human leukemia has been significantly improved by ABL tyrosine kinase inhibitors (TKIs), but they are not curative for most patients and relapses are frequently associated with BCR-ABL mutations, warranting new targets for improved treatments. We have now demonstrated that protein expression of human estrogen receptor alpha 36 (ERα36), an alternative splicing variant of human estrogen receptor alpha 66 (ERα66), is highly increased in TKI-insensitive CD34+ chronic myeloid leukemia (CML) cells and BCR-ABL-T315I mutant cells, and is abnormally localized in plasma membrane and cytoplasm. Interestingly, new pre-clinically-validated analogs of Icaritin (SNG162 and SNG1153), which target abnormal ERα36 activity, inhibit cell growth and induce apoptosis of BCR-ABL+ leukemic cells, particularly BCR-ABL-T315I mutant cells. A combination of SNG inhibitors and TKI selectively eliminates treatment-naïve TKI-insensitive stem/progenitor cells while sparing healthy counterparts. Oral TKI dasatinib combined with potent SNG1153 inhibitor effectively eliminates infiltrated BCR-ABL+ blast cells and enhances survival of mice. Importantly, a unique mechanism of SNG inhibition was uncovered by demonstrating a marked interruption of the BCR-ABLTyr177-GRB2 interaction, leading to inhibition of the downstream RAS/MAPK pathway. This new combination therapy may lead to more effective disease eradication, especially in patients at high risk of TKI resistance and disease progression.
    [Abstract] [Full Text] [Related] [New Search]